Preparation of (all-E)- and (11Z)-12-haloretinals and (11Z,13Z)- and (13Z)-14-haloretinals by the C15 + C5 route - Exploring the possibility of preparing any retinoid rationally chemically modified at any position in the conjugated t

Article abstract of DOI:10.1002/ejoc.200400488

In this paper we describe how chemically modified ylides can be prepared by electrophilic substitution in a simple way. A subsequent Horner-Emmons reaction gives access to (all-E)- and (HZ)-12-chloro-, -12-bromo-, and -12-iodoretinal. It could be expected

Full text of DOI:10.1002/ejoc.200400488

FULL PAPER
Preparation of (all-E)- and (11Z)-12-Haloretinals and (11Z,13Z)- and (13Z)-
14-Haloretinals by the C15 ؉ C5 Route ؊ Exploring the Possibility of
Preparing any Retinoid Rationally Chemically Modified at any Position in the
Conjugated Tail
Yajie Wang[a] and Johan Lugtenburg*[a]
Keywords: Electrophiles / Nucleophiles / Selectfluor / DAST / Fluororetinals
In this paper we describe how chemically modified ylides can
be prepared by electrophilic substitution in a simple way. A
subsequent Horner−Emmons reaction gives access to (all-E)-
and (11Z)-12-chloro-, -12-bromo-, and -12-iodoretinal. It
could be expected that many more retinals chemically modi-
fied at the 12-position could be prepared in this manner. Se-
extended to a whole range of electrophilic-substitution reac-
tions. We also developed a novel method to prepare 4-hy-
droxy-substituted Horner−Emmons derivatives, which could
be converted into the 4-fluoro derivatives by reaction with
(diethylamino)sulfur trifluoride (DAST). This system could
simply be converted into 12-fluororetinal in the (all-E)- and
lectfluor, a good reagent for introducing a fluorine atom by (11Z)-isomeric forms and we think that this strategy has a
electrophilic substitution, does not give the 12-fluororetinal good scope to prepare a whole series of 12-modified retinals.
system. However, 14-fluororetinal is simply available by re- We have also explored the essential steps to give access to
action of the anion with Selectfluor. Cl, Br and I atoms were retinoids modified at any position of the conjugated chain.
also introduced at the 14-position of retinal both in the
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
(11Z,13Z)- and (13Z)-isomeric forms. This strategy could be
Germany, 2004)
Introduction
various chemical modifications at the 9-position of the con-
jugated chain.[7,8] These molecules are designed to obtain
essential information about the role of the 9-methyl group
(or other substituent), which plays a pivotal role in rhodop-
sin and isorhodopsin as the G-protein-coupled light recep-
tor.
Rhodopsin is the G-protein-coupled photoreceptor in the
retinae of vertebrates that initiates the visual signal trans-
duction cascade in dim-light vision. It is considered a para-
digm for the super family of seven transmembrane α-helix
G-protein-coupled receptors (GPCRs),[1] which comprises
a physiologically widespread and pharmacologically very
significant class of signal mediators.[1Ϫ4] GPCRs trigger a
wide variety of physiological processes that involve signal-
ling by neurotransmitters, hormones and neuropeptides and
are therefore one of the major pharmaceutical targets for
pharmacological intervention or in human (animal) pathol-
ogy.[4]
We recently published a solid-state NMR study in which
we established the charge distribution over each of the olef-
inic carbon atoms in the (11Z)-retinylidene chromophore,[5]
together with the precise conformation of the central part
of the chromophore.[6] This novel information, with atomic
resolution, allows the study of systems with rationally de-
signed chemical changes in the chromophore.
The target of the present study was to prepare (all-E)-
and (11Z)-retinals with a halogen substituent at the 12-po-
sition in order to elucidate the role of the 12-H (or other
substituent) in the primary step in rhodopsin photochemis-
try (conversion of the electronically excited rhodopsin chro-
mophore into the ground state of bathorhodopsin, the pri-
mary photochemical product). This step is completed in 200
fs after the absorption of a photon by rhodopsin;[9] it is
the fastest photochemical reaction thus far known. Various
groups have assumed that an out-of-plane rotation of 12-H
is the essential step in this process.[10Ϫ12] In the region of
such ultrafast reactions, the energy involved to initiate such
rapid processes may be considerable. The chromophore of
rhodopsin has a torsion angle of about 45° around the
12Ϫ13 bond (Figure 1).[13] A rotation of about 90° of
this hydrogen means that the 11Ϫ12 cis bond will be moved
into the 11Ϫ12 transoid region of 135°. To effect a H-
rotation within 200 fs over 90°, the energy needed to
generate this angular momentum per molecule is given by
1/2(mHR2C12-H)π2/4.[14] For a grammol, using the known
constants mH ϭ 1.66 ϫ 10Ϫ27 kg, NA ϭ 6.02 ϫ 1023 molϪ1
Our first target in this program was a new strategy to
synthesise (all-E)-, (9Z)- and (11Z)-α- and -β-retinals with
[a]
Leiden Institute of Chemistry, Leiden University, Gorlaeus
Laboratories,
P. O. Box 9502, 2300 RA Leiden, The Netherlands
Fax: (internat.) ϩ 31-71-5274488
E-mail: Lugtenbu@chem.leidenuniv.nl
5100
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
DOI: 10.1002/ejoc.200400488
Eur. J. Org. Chem. 2004, 5100Ϫ5110

Preparation of a Series of 12- and 14-Haloretinals
FULL PAPER
and R ϭ 1 ϫ 10Ϫ10 m, this formula gives a value of 0.3 equiv. of trimethylsilyl chloride, gave the 2-trimethylsilyl de-
kJ·molϪ1; repeating the same calculations for 12-F, 12-Cl, rivative 6.[17,18] It is well known that allylic silyl compounds
12-Br and 12-I gives values of 2.4 kcal·molϪ1, 7.4 can react with electrophiles to introduce a substituent at the
kcal·molϪ1, 20.4 kcal·molϪ1 and 39.6 kcal·molϪ1, respec- 4-position, with concomitant expulsion of the trimethylsilyl
tively. For the latter two situations the value is much higher group and shift of the double bond to the 2Ϫ3 position.[17]
than the 15 kcal difference between electronically excited Thus, treatment with
rhodopsin and ground-state bathorhodopsin.[15] This HornerϪEmmons reagent, and addition of 1 equiv. of β-
means that the kinetics of the bromo and iodo system (ionylidene)acetaldehyde (7) provided the
1
equiv. of base gave the
should be at least one order of magnitude slower if the same HornerϪWadsworthϪEmmons reaction product. The syn-
process still occurs. It is also known that in the photochem- thesis of (all-E)-7 and its corresponding nitrile has been de-
istry of rhodopsin, there is a linear relationship between the scribed by us before.[7] Treatment of 6 with N-chlorosuccini-
ultrafast kinetics and the quantum yield.[16] It is clear that mide and subsequent addition of 7 gave a mixture of (all-
studying the femtosecond kinetics and the quantum yield E)-12-chlororetinonitrile (all-E)-8 and (11Z)-12-chlororeti-
of bathorhodopsin formation with a series consisting of the nonitrile (11Z)-8 (all-E/11Z, 3:2). Similarly, treatment of 6
native system and the 12-F, 12-Cl, 12-Br and 12-I deriva- with N-bromosuccinimide and subsequent addition of 7
tives will give direct information about the role of the sub- gave a mixture of (all-E)-12-bromoretinonitrile (all-E)-9
stituent in the photochemical process in rhodopsin photo- and (11Z)-12-bromoretinonitrile (11Z)-9 (all-E/11Z, 3:2),
chemistry.
and treatment of 6 with N-iodosuccinimide and subsequent
addition of 7 gave a mixture of (all-E)-12-iodoretinonitrile
(all-E)-10 and (11Z)-12-iodoretinonitrile (11Z)-10 (all-E/
11Z, 3:2). This synthesis could be achieved in a one-pot
procedure. The reaction mixture was then treated with
aqueous sodium hydrogen carbonate. The resulting mixture
was extracted with diethyl ether, the solution dried with
MgSO4 and the solvent was evaporated under reduced
pressure. Pure (all-E)-8 and (11Z)-8, (all-E)-9 and (11Z)-9
and (all-E)-10 and (11Z)-10, respectively, were obtained in
high yields by a preparative HPLC procedure. Subsequent
reduction with DIBAL-H led to the corresponding retinals,
although this synthesis had to be carried out for the (11Z)-
9-halo system by a previously reported method.[7] (all-E)-8
and (11Z)-8 have been described before; their spectroscopic
properties are in complete agreement with those pub-
lished.[11] This method will also be applicable for many
other (11Z)-12-substituted retinal systems by varying the
electrophile. We hoped that the corresponding 12-fluoro de-
rivatives could be prepared by treating 6 with Selectfluor
[1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane
bis(tetrafluoroborate)][19] as this commercially available
compound allows the introduction of a fluoro substituent
in an electrophilic-substitution reaction. However, treat-
ment of 6 with 1 equiv. of Selectfluor did not give any
reaction at all.
Figure 1. Structure of the retinylidene chromophore in the active
site of rhodopsin (X ϭ H) and its 12-F, 12-Cl, 12-Br and 12-I
derivatives; the dihedral angle around the 12Ϫ13 bond is about
45°; the arrow indicates the direction of rotation of the 12-X sub-
stituent that converts the electronically excited state of rhodopsin
into the ground-state primary photochemical product bathorho-
dopsin
In this paper we describe a synthetic strategy to prepare
12-fluoro-, 12-chloro-, 12-bromo-, and 12-iodoretinal with
both the (all-E) and (11Z) configurations. Due to the pri-
ority of halogens in IUPAC nomenclature, (all-E)-12-halor-
etinals are the systems that will provide the required 12-
halorhodopsins. Based on this chemistry, we have also pre-
pared 14-fluoro-, 14-chloro-, 14-bromo- and 14-iodoretinal
with (11Z,13Z) and (13Z) configurations. In this case, the
(11Z,13Z)-14-haloretinals are the precursors to form the
14-halorhodopsins.
In order to obtain the needed halo derivatives, the anion
5 was extended with N-chloro-, N-bromo- or N-iodosuccin-
imide to give mixtures of (all-E)-8 and (11Z)-8, (all-E)-9
and (11Z)-9 and (all-E)-10 and (11Z)-10, respectively, as
well as the corresponding 14-chlorinated (11Z,13Z)-11 and
(13Z)-11, 14-brominated (11Z,13Z)-12 and (13Z)-12 and
14-iodinated (11Z,13Z)-13 and (13Z)-13, respectively. This
means that the electrophilic attack of the halo atom on 5 is
not selective. The ratio of attack at the 2-position versus the
4-position in 5 is about 2:3. A similar situation holds for
The possibilities to chemically modify any retinoid on
any specific positions in the ethylenic linkage conjugated
tail-end are explored.
Results and Discussion
For the synthesis of (all-E)- and (11Z)-12-haloretinals, we the corresponding Br and I systems 9, 12 and 10, 13. The
used the known compound 4-(diphenoxyphosphoryl)-3- ratio of attack of the bromo on positions 2 and 4 is about
methyl-2-butenenitrile (5)[7] as synthon (Scheme 1). Treat- the same as in the chloro case. In the case of iodo substi-
ment of 5 with 1 equiv. of NaH in THF gave the corre- tution it is 1:3. These systems were separated by preparative
sponding anion which, upon subsequent treatment with 1 HPLC techniques.
Eur. J. Org. Chem. 2004, 5100Ϫ5110
www.eurjoc.org
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
5101

Y. Wang, J. Lugtenburg
FULL PAPER
Scheme 1. Preparation of (all-E)-12-chlororetinal, (all-E)-12-bromoretinal, (all-E)-12-iodoretinal and their (11Z) isomers, together with
(13Z)-14-chlororetinal, (13Z)-14-bromoretinal, (13Z)-14-iodoretinal and their (11Z,13Z) isomers
The nitriles 8Ϫ13 were reduced with DIBAL-H, as dis- at either the 2- or 4-position in the allylic anion: in the case
cussed before, to give the corresponding (11Z,13Z)- and of reaction with trimethylsilyl chloride or Selectfluor the
(13Z)-14-halo-substituted retinals. In the case of the 14- attack only takes place at the least hindered 2-position next
iodo system, the 14-iodo atom is partially substituted by a to the very small CN group, indicating that these sterically
hydrogen atom during the reduction. We have encountered very demanding reagents only attack at 2-position and not
this iodine loss during DIBAL-H reduction before and this at all at 4-position, linked to the bulky phosphonate group.
fact has been previously reported.[20] Pure (11Z,13Z)-17 In the case of N-iodosuccinimide even more attack of the
and (13Z)-17 were obtained in an isomeric ratio of 3:2 by iodo takes place at position 2 than in the case of the other
preparative HPLC.
halogen reagents in a 2/4 selecting ratio of 1:3.
Taking into account these results, we decided to explore
We reasoned that Selectfluor might also react with the
anion of 5 (Scheme 2). However, in the case of the reaction the possibility of simple site-directed introduction of sub-
with trimethylsilyl chloride, complete fluorination occurred stituents. 2-Substituted 4-(diphenoxyphosphoryl)-3-methyl-
only at the 2-position to give a mixture of (11Z,13Z) iso- 2-butenenitriles should be simply accessible by the reactions
mers of 14-F-19 and (13Z)-14-F-19. After the coupling re- depicted in Scheme 3. 2-(Diethoxyphosphoryl)acetonitrile
action with β-(ionylidene)acetaldehyde (7), a DIBAL-H re- was treated with 1 equiv. of LDA in THF to give the corre-
duction gave (11Z,13Z)-14-F-retinal 20 and its (13Z) iso- sponding anion, which was allowed to react with Sel-
mer. It is clear from our results that electronic and steric ectfluor to give the 2-fluoro derivative. Subsequent ad-
factors have a strong influence on the electrophilic attack dition of a second equivalent of LDA and then 1 equiv. of
Scheme 2. Preparation of (11Z,13Z)-14-fluororetinal and (13Z)-14-fluororetinal
5102
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2004, 5100Ϫ5110

Preparation of a Series of 12- and 14-Haloretinals
FULL PAPER
Scheme 3. Top: preparation of 4-(diphenylphosphoryl)-2-fluoro-3-methyl-2-butenenitrile by a method that allows chemical modification
at positions 2 and 3; bottom: simple preparation of 19-fluoro-β-(ionylidene)acetaldehyde
1-chloroacetone (R ϭ CH3) led to 4-chloro-2-fluoro-3- bond attached to the nitrile was not affected. We have de-
methylbut-2-ene (24; R ϭ CH3, X ϭ F). Arbuzov reaction scribed this type of selectivity before.[21] Treatment of this
with methyl diphenyl phosphite then gave 4-(diphenoxyphos- epoxide with a catalytic amount of perchloric acid in water
phoryl)-2-fluoro-3-methyl-2-butenenitrile (25; R ϭ CH3, gave the 4,5-diol 28 after extraction into a 10:1 diethyl
X ϭ F). A HornerϪEmmons reaction of the anion of 25 ether/acetonitrile mixture. After subsequent evaporation of
(R ϭ CH3, X ϭ F) with β-(ionylidene)acetaldehyde gave a the solvent, 28 was dissolved in CH2Cl2. Oxidative cleavage
mixture of (11Z,13Z)-19 and (13Z)-19, as described above. of 28 with lead tetraacetate gave the 4-oxonitrile 29, which
Based on our earlier work[28] it is known that the reacted with dialkyl phosphite to give (1-hydroxyalkyl)phos-
HornerϪEmmons reaction of chloromethyl keto systems phonates in high yield.[22,23] The 4-oxonitrile 29 reacted
with the 2-phosphononitrile anion is very general, as is the with diphenyl phosphite (diphenyl phosphonate according
subsequent Arbuzov reaction, which means that this route to the tautomer shown in Scheme 4) to give 4-(di-
permits the synthesis of derivatives of 25 with many combi- phenoxyphosphoryl)-4-hydroxy-3-methyl-2-butenenitrile
nations of substituents (R and X) at positions 2 and 3, This (30) in high yield. Phosphonate 30 was converted into a mix-
means that a whole library of 13- and 14-substituted (11Z)- ture of the required compounds 31 and 18 (Scheme 4) upon
and (all-E)-retinals will be available in this way. It could treatment with (diethylamino)sulfur trifluoride (DAST), al-
also be expected that anions of type 25 can be chlorinated, though alkyl (1-hydroxyalkyl)phosphonates react with DAST
brominated and iodinated, giving access to retinal chemi- only by γ-fluorination.[24] Treatment of β-(ionylidene)acetal-
cally modified at position 14.
dehyde with the anion of 31 gave a mixture of the correspond-
The only drawback in this general strategy is that we ing 12-F-retinonitriles, which were separated by preparative
don’t have a method to introduce the fluoro substituent at HPLC. Subsequent careful DIBAL-H reduction gave pure
position 12 in (11Z)- and (all-E)-retinal. In order to effect (all-E)-12-fluororetinal (all-E)-1 or (11Z)-12-fluororetinal
this we explored a different approach. Commercially avail- (11Z)-1. The spectroscopic data of (all-E)-1 and (11Z)-1 are
able 4-methyl-3-penten-2-one (26; Scheme 4) was treated in agreement with those published in the literature.[25]
with the anion of 2-(diethoxyphosphoryl)acetonitrile (21) in
The allylic OH group in 30, which can be converted into
THF to yield 3,5-dimethyl-2,4-hexadienenitrile (27). Treat- the corresponding fluoride by nucleophilic substitution
ment of 27 with m-chloroperbenzoic acid (mCPBA) led, with DAST, could also be replaced by a host of substituents
after removal of the m-chlorobenzoic acid by washing with by a Mitsunobu reaction.
aqueous sodium hydroxide solution, to the corresponding
The conversion of 26 can be carried out with various sub-
epoxide. Under these experimental conditions the double stituted (diethoxyphosphoryl)acetonitrile anions 22, which
Scheme 4. Preparation of (all-E)-12-fluororetinal and (11Z)-12-fluororetinal
www.eurjoc.org
Eur. J. Org. Chem. 2004, 5100Ϫ5110
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
5103

Y. Wang, J. Lugtenburg
FULL PAPER
results in conjugated nitriles of type 27 with various sub- sphoryl)-4-hydroxy-3-methyl-2-butenenitrile by a nucleo-
stituents at C-2. This means that 4-(diphenoxyphosphoryl)- philic reaction with (diethylamino)sulfur trifluoride
2-butenenitrile systems will be accessible with various sub- (DAST). The required 4-fluoro HornerϪEmmons reagent
stituents at carbon atoms 2, 3 and 4 (Scheme 4).
can be prepared in a reasonable yield. In this way, (all-E)-
It is gratifying that the presence of substituents at posi- and (11Z)-12-F-retinals can be made in a simple way. The
tions 2 and 4 does not change the fundamental thermo- chloro, bromo and iodo synthons also easily prepared to
dynamic and kinetic factors, such that only reaction prod- give the whole set of 12-halo-substituted derivatives. Based
ucts with (11Z) and (11E) conformations are formed. In a on the ease of access of these systems both with electro-
previous paper we have reported a strategy to convert β- philic and nucleophilic reagents in a rational site-directed
and α-cyclocitral into (all-E)-, (11Z)-retinal and α-retinal. way, it is clear that a whole library of various chemically
This means that the chemically modified HornerϪEmmons modified HornerϪEmmons reagents is now easily access-
reagents reported here will allow an entry to (all-E)- and ible by this route, which allows the entry to various site-
(11Z)-retinals chemically modified at positions 8, 9, 10, 12, directed chemically modified retinoids. The possibilities to
13 and 14 of the conjugated chain. Multisite-directed extend this strategy to various positions in the carbon chain
rationally designed chemical modification could also be of retinoids have been explored and discussed.
used
with
the
present
chemically
modified
HornerϪEmmons reagents. In our earlier study, we devel-
oped an alternative method to introduce chemical modifi-
cations in the conjugated chain at positions 9 and 13, which
can easily be extended to positions 7 and 11. The only posi-
Experimental Section
General: All light-sensitive reactions were carried out in dim red
tions where no simple chemical modification has been real- light (λ Ͼ 620 nm) or in the dark. All experiments were carried
out under dry nitrogen or argon. Commercially available starting
materials N-chlorosuccinimide, N-bromosuccinimide, N-iodosucci-
nimide, 4-methyl-3-pentene-2-one, 2-(diethoxyphosphoryl)aceton-
itrile, m-chloroperbenzoic acid, diphenyl phosphite (diphenyl
phosphonate) and trimethylsilyl chloride, etc. were purchased
from Sigma Aldrich. 1-Chloromethyl-4-fluoro-1,4-diazoniabicyclo-
[2.2.2]octane bis(tetrafluoroborate) (ϭ Selectfluor) and (diethyl-
amino)sulfur trifluoride (DAST) were purchased from Acros. All
reagents were used without further purification, unless stated
otherwise. In all cases, the chemically pure or higher quality grade
ized thus far are 19 and 20. In order to show that these
positions can also be made accessible, we carried out the
reactions depicted in Scheme 3. β-(Ionylidene)acetonitrile
(32) was treated with LDA in THF at Ϫ60 °C, and the
resulting anion was reacted with trimethylsilyl chloride to
give the allylic silyl derivative 33. Treatment of 33 with Sel-
ectfluor gave the 6-F-nitrile, which was subsequently re-
duced with DIBAL-H to obtain the 6-F-(ionylidene)acetal-
dehyde 34.The 6-F-(ionylidene)acetonitrile and the corre-
sponding aldehyde have been reported before.[26] The NMR of the chemicals was used. Sodium hydride refers to a 60% suspen-
sion in mineral oil. Petroleum ether refers to the fraction with a
boiling range of 40Ϫ60 °C. Dry solvents and reagents were stored
under dry argon. Dry THF was freshly distilled over sodium. Dry
petroleum ether and dry diethyl ether were prepared by distilling
over phosphorus pentoxide and were stored over sodium wire. Dry
diisopropylamine and dichloromethane were freshly prepared by
distilling over freshly grinded calcium hydride and stored over mo-
lecular sieves (4 A). Silica gel column chromatography was per-
formed using Merck silica gel 60 (0.040Ϫ0.063 mm, 230Ϫ400
mesh). HPLC purification was performed with an LKB Bromma
spectra of our materials are in agreement with those re-
ported earlier.[26] Hence, with this simple allylic trimethyl-
silyl derivative 33, Selectfluor gives the expected result, as
has been described before.[27] This strategy could possibly
be extended to other electrophiles. As the same type of fac-
tors rule the chemistry of the 13-methyl group in retinonitr-
ile to those in β-(ionylidene)acetonitrile, atom 20 in retino-
ids can also be chemically modified. Based on the explora-
tory work in this paper, we can conclude that all positions
˚
in the conjugated chain of retinoids can now be rationally system using a preparative Zorbax silica gel column 21.2 mm ϫ
25 cm (Du Pont, Delaware). The eluent was hexane/diethyl ether
(97/3, v/v). 1H NMR spectra were recorded with a Bruker DPX-
300 spectrometer operating at 300.13 MHz and were internally ref-
erenced to the proton of deuterated methanol (δ ϭ 3.30 ppm) or
tetramethylsilane (TMS, δ ϭ 0.00 ppm). 13C NMR spectra were
recorded at 75.5 MHz and were internally referenced to the carbon
signal of deuterated methanol (δ ϭ 49.0 ppm) or deuterated chloro-
form (δ ϭ 77.0 ppm).
chemically modified and multi combinations, if not all
chemical modifications, can be introduced in a rational
manner.
Conclusion
The anion of 4-(diphenoxyphosphoryl)-3-methyl-2-but-
enenitrile gives the 2-trimethylsilyl derivative upon treat-
ment with trimethylsilyl chloride. This system reacts with
electrophilic halogenating agents to generate the corre-
sponding 4-halogenated compounds, which, in a sub-
sequent HornerϪEmmons reaction, give (all-E)- and (11Z)-
12-haloretinals. The corresponding 12-F derivative could
not be prepared by this way. Due to the importance of site-
directed fluorinated systems in biology, medicine and phar-
(11Z)-12-Chlororetinal [(11Z)-2]: A solution of 4-(diphenoxyphos-
phoryl)-3-methyl-2-butenenitrile (5; 122 mg, 0.39 mmol) in THF
(5 mL) was added dropwise to sodium hydride (16 mg, 0.39 mmol)
at 0 °C. The mixture was stirred at 0 °C for 1 h. Trimethylsilyl
chloride (43 mg, 0.39 mmol) in THF (10 mL) was added and stir-
ring was continued at 0 °C for 1 h. After that, NCS (52 mg,
0.39 mmol) in THF (5 mL) was added. After stirring at 0 °C for
an additional 1 h, sodium hydride (15 mg, 0.37 mmol) in THF
(10 mL) was added to the mixture. The temperature was allowed
macy, we have developed a new access to 4-(diphenoxypho- to gradually rise to room temperature. After addition of β-(ionylid-
5104  2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.eurjoc.org
Eur. J. Org. Chem. 2004, 5100Ϫ5110

Preparation of a Series of 12- and 14-Haloretinals
FULL PAPER
ene)acetaldehyde (7; 85 mg, 0.39 mmol) in THF (5 mL), the reac- bromoretinonitrile and (all-E)-12-bromoretionitrile isomer in an
tion mixture was quenched with saturated aqueous NaHCO3. The isomeric ratio of 2:3. Pure (11Z)-12-bromoretinonitrile, (11Z)-9
aqueous layer was extracted with diethyl ether (2 ϫ 15 mL) and
(49 mg) and pure (all-E)-12-bromoretinonitrile, (all-E)-9 (73 mg)
the combined organic layers were washed with brine, dried with a were obtained by preparative HPLC (93% combined yield). Sub-
mixture of K2CO3 and MgSO4 (1:9, wt/wt), filtered and concen- sequent DIBAL-H (0.34 mmol, 1.0  in hexane) reduction of the
trated under reduced pressure. The crude product contained (11Z)-
12-chlororetinonitrile and (all-E)-12-chlororetinonitrile isomer in (11Z)-3; 46 mg (94%). H NMR (300.1 MHz, CD3OD): δ ϭ 1.03
pure (11Z)-12-bromoretinonitrile (49 mg, 0.14 mmol) yielded
1
an isomeric ratio of 2:3. Pure (11Z)-12-chlororetinonitrile (11Z)-
8 (44 mg) and (all-E)-12-chlororetinonitrile (all-E)-8 (66 mg) were
obtained by preparative HPLC (93%). The pure (11Z)-12-chlorore-
tinonitrile (44 mg, 0.14 mmol) was dissolved in dry petroleum ether
and cooled to Ϫ80 °C. DIBAL-H (0.37 mmol, 1.0  in hexane)
was added and the resulting solution was stirred and warmed to
(s, 6 H, H-16, H-17), 1.43 (m, 2 H, H-2), 1.54 (m, 2 H, H-3), 1.71
(s, 3 H, H-18), 1.96 (s, 3 H, H-19), 2.01 (m, 2 H, H-4), 2.28 (s, 3
3
H, H-20), 6.01 (d, JH14,H15 ϭ 7.9 Hz, 1 H, H-14), 6.14 (d,
3
3JH8,H7 ϭ 16.1 Hz, 1 H, H-8), 6.37 (d, JH10,H11 ϭ 11.5 Hz, 1 H,
3
3
H-10), 6.57 (d, JH7,H8 ϭ 16.1 Hz, 1 H, H-7), 7.29 (d, JH11,H10
ϭ
3
11.5 Hz, 1 H, H-11), 10.2 (d, JH15,H14 ϭ 7.9 Hz, 1 H, H-15) ppm.
Ϫ40 °C in 1 h. Then homogeneous basic wet alumina (0.65 g; 13C NMR (75.5 MHz, H-noise-decoupled, CD3OD): δ ϭ 13.1 (C-
1
Al2O3/water, 5:1, wt/wt) was added and the mixture was stirred for
an additional hour at 0 °C. The reaction mixture was dried with
K2CO3/MgSO4 (1:9, wt/wt). All solids were filtered off and washed
with diethyl ether, yielding (11Z)-12-chlororetinal [(11Z)-2]; 42 mg
(94%). 1H NMR (300.1 MHz, CD3OD): δ ϭ 1.04 (s, 6 H, H-16, H-
17), 1.49 (m, 2 H, H-2), 1.64 (m, 2 H, H-3), 1.72 (s, 3 H, H-18),
2.03 (m, 2 H, H-4), 2.06 (s, 3 H, H-19), 2.25 (s, 3 H, H-20), 5.76
(d, JH14,H15 ϭ 7.7 Hz, 1 H, H-14), 6.21 (d, JH8,H7 ϭ 16.1 Hz, 1
H, H-8), 6.45 (d, 3JH7,H8 ϭ 16.1 Hz, 1 H, H-7), 6.94 (d, 3JH10,H11 ϭ
11.5 Hz, 1 H, H-10), 7.23 (d, 3JH11,H10 ϭ 11.5 Hz, 1 H, H-11), 10.2
(d, 3JH15,H14 ϭ 7.7 Hz, 1 H, H-15) ppm. 13C NMR (75.5 MHz, 1H-
noise-decoupled, CD3OD): δ ϭ 12.7 (C-19), 20.1 (C-3), 20.3 (C-
20), 21.3 (C-18), 29.4 (C16, C17), 34.0 (C-4), 35.2 (C-1), 40.7 (C-
2), 124.1 (C-14), 130.4 (C-11), 130.6 (C-10), 131.1 (C-5), 132.6 (C-
7), 133.6 (C-12), 138.8 (C-6), 139.0 (C-8), 141.9 (C-9), 156.2 (C-
13), 191.2 (C-15) ppm.
19), 20.3 (C-20), 20.5 (C-3), 22.1 (C-18), 29.3 (C16, C17), 34.0 (C-
4), 35.1 (C-1), 40.7 (C-2), 127.6 (C-7), 130.7 (C-14), 131.1 (C-5),
131.4 (C-11), 133.3 (C-8), 134.6 (C-10), 137.2 (C-12), 138.3 (C-6),
144.9 (C-9), 158.7 (C-13), 192.6 (C-15) ppm.
(all-E)-12-Bromoretinal [(all-E)-3]: The procedure was the same as
that described for the preparation of (all-E)-8. DIBAL-H
(0.51 mmol, 1.0  in hexane) reduction of pure (all-E)-12-bromore-
tinonitrile (all-E)-9 (73 mg, 0.2 mmol) gave (all-E)-3; 69 mg (95%).
1H NMR (300.1 MHz, CD3OD): δ ϭ 1.05 (s, 6 H, H-16, H-17),
1.46 (m, 2 H, H-2), 1.52 (m, 2 H, H-3), 1.68 (s, 3 H, H-18), 1.92
(s, 3 H, H-19), 1.99 (m, 2 H, H-4), 2.36 (s, 3 H, H-20), 5.95 (d,
3
3
3
3JH14,H15 ϭ 7.7 Hz, 1 H, H-14), 6.03 (d, JH8,H7 ϭ 16.1 Hz, 1 H,
3
3
H-8), 6.34 (d, JH7,H8 ϭ 16.1 Hz, 1 H, H-7), 6.87 (d, JH10,H11
ϭ
11.6 Hz, 1 H, H-10), 7.07 (d, 3JH11,H10 ϭ 11.6 Hz, 1 H, H-11), 10.0
(d, 3JH15,H14 ϭ 7.7 Hz, 1 H, H-15) ppm. 13C NMR (75.5 MHz, 1H-
noise-decoupled, CD3OD): δ ϭ 12.7 (C-19), 20.1 (C-20), 20.3 (C-
3), 22.3 (C-18), 30.3 (C16, C17), 33.9 (C-4), 35.1 (C-1), 40.7 (C-2),
125.4 (C-7), 130.4 (C-11), 130.9 (C-14), 131.0 (C-5), 132.8 (C-8),
134.6 (C-10), 136.4 (C-12), 138.2(C-6), 145.2 (C-9), 160.2 (C-13),
194.7 (C-15) ppm.
(all-E)-12-Chlororetinal [(all-E)-2]: The (all-E)-12-Chlororetinonitr-
ile (66 mg, 0.21 mmol) was dissolved in dry petroleum ether and
cooled to Ϫ80 °C. DIBAL-H (0.52 mmol, 1.0  in hexane) was
added and the resulting solution was stirred and warmed to Ϫ40
°C over 1 h. Subsequently, homogeneous basic wet alumina (0.91 g;
Al2O3/water, 5:1, wt/wt) was added and the mixture was stirred at
0 °C for an additional 1 hour. The reaction mixture was dried by
adding a mixture K2CO3 and MgSO4 (1:9, wt/wt). All solids were
filtered off and washed with diethyl ether, yielding (all-E)-12-chlo-
roretinal [(all-E)-2]; 63 mg (95%). 1H NMR (300.1 MHz, CD3OD):
δ ϭ 1.01 (s, 6 H, H-16, H-17), 1.46 (m, 2 H, H-2), 1.61 (m, 2 H,
H-3), 1.64 (s, 3 H, H-18), 1.96 (s, 3 H, H-19), 2.00 (m, 2 H, H-4),
(11Z)-12-Iodoretinal [(11Z)-4]: The procedure was the same as that
described for the preparation of (11Z)-2 and (all-E)-2 by adding 4-
(diphenoxyphosphoryl)-3-methyl-2-butenenitrile
(5;
122 mg,
0.39 mmol) in THF (5 mL) dropwise to sodium hydride (16 mg,
0.39 mmol) at 0 °C. Subsequently, trimethylsilyl chloride (43 mg,
0.39 mmol) in THF (10 mL) was added, followed by NIS (88 mg,
0.39 mmol) in THF (5 mL). Sodium hydride (15 mg, 0.37 mmol) in
THF (10 mL) was then added to the mixture and the temperature
was allowed to gradually rise to room temperature. β-(Ionylidene)a-
cetaldehyde (7; 85 mg, 0.39 mmol) in THF (5 mL) was then added.
After work up, the crude product was found to contain (11Z)-12-
iodoretinonitrile and (all-E)-12-retinonitrile isomers in an isomeric
ratio of 2:3. Pure (11Z)-12-iodoretinonitrile [(11Z)-10] (58 mg) and
pure (all-E)-12-iodoretinonitrile [(all-E)-10] (88 mg) were obtained
by preparative HPLC (96%). DIBAL-H (0.37 mmol, 1.0  in hex-
ane) reduction of the pure (11Z)-12-iodoretinonitrile (58 mg,
0.14 mmol) gave (11Z)-12-iodoretinal [(11Z)-4]; 55 mg (94%). 1H
NMR (300.1 MHz, CD3OD): δ ϭ 1.01 (s, 6 H, H-16, H-17), 1.48
(m, 2 H, H-2), 1.64 (m, 2 H, H-3), 1.68 (s, 3 H, H-18), 1.93 (s, 3
3
2.36 (s, 3 H, H-20), 6.00 (d, JH14,H15 ϭ 7.7 Hz, 1 H, H-14), 6.05
3
3
(d, JH8,H7 ϭ 16.1 Hz, 1 H, H-8), 6.09 (d, JH10,H11 ϭ 11.1 Hz, 1
3
H, H-10), 6.33 (d, JH7,H8 ϭ 16.1 Hz, 1 H, H-7), 6.90 (d,
3JH11,H10 ϭ 11.9 Hz, 1 H, H-11), 10.1 (d, JH15,H14 ϭ 7.6 Hz, 1 H,
3
H-15) ppm. 13C NMR (75.5 MHz, H-noise-decoupled, CD3OD):
1
δ ϭ 12.7 (C-19), 20.3 (C-20), 20.4 (C-3), 21.9 (C-18), 29.4 (C16,
C17), 34.0 (C-4), 35.1 (C-1), 40.7 (C-2), 124.1 (C-14), 124.1 (C-10),
130.2 (C-11), 131.1 (C-5), 131.3 (C-7), 137.3 (C-12), 137.8 (C-8),
138.8 (C-6), 141.9 (C-9), 157.0 (C-13), 193.6 (C-15) ppm.
(11Z)-12-Bromoretinal [(11Z)-3]: The procedure was the same as
that described for the preparation of (11Z)-2 and (all-E)-2 by ad-
H, H-19), 2.02 (m, 2 H, H-4), 2.23 (s, 3 H, H-20), 5.75 (d,
ding 4-(diphenoxyphosphoryl)-3-methyl-2-butenenitrile (5; 122 mg, 3JH14,H15 ϭ 7.8 Hz, 1 H, H-14), 6.02 (d, JH10,H11 ϭ 11.8 Hz, 1 H,
3
3
3
0.39 mmol) in THF (5 mL) dropwise to sodium hydride (16 mg,
H-10), 6.06 (d, JH8,H7 ϭ 16.1 Hz, 1 H, H-8), 6.36 (d, JH7,H8 ϭ
3
0.39 mmol) at 0 °C. Subsequently, trimethylsilyl chloride (43 mg,
16.1 Hz, 1 H, H-7), 7.28 (d, JH11,H10 ϭ 11.8 Hz, 1 H, H-11), 10.1
0.39 mmol) in THF (10 mL) was added followed by NBS (69 mg, (d, 3JH15,H14 ϭ 7.8 Hz, 1 H, H-15) ppm. 13C NMR (75.5 MHz, 1H-
0.39 mmol) in THF (5 mL). After addition of further sodium hy-
dride (15 mg, 0.37 mmol) in THF (10 mL), the temperature was
allowed to gradually rise to room temperature. β-(Ionylidene)acet-
noise-decoupled, CD3OD): δ ϭ 12.6 (C-19), 20.3 (C-3), 21.6 (C-
20), 21.8 (C-18), 29.5 (C16, C17), 34.1 (C-4), 35.3 (C-1), 40.7 (C-
2), 95.1 (C-12), 125.9 (C-10), 129.8 (C-14), 131.2 (C-7), 131.0 (C-
aldehyde (7; 85 mg, 0.39 mmol) in THF (5 mL) was then added. 5), 138.5 (C-8), 138.7 (C-6), 140.7 (C-9), 142.4 (C-11), 162.5 (C-
After work up, the crude product was found to contain (11Z)-12- 13), 194.6 (C-15) ppm.
Eur. J. Org. Chem. 2004, 5100Ϫ5110
www.eurjoc.org
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
5105

Y. Wang, J. Lugtenburg
FULL PAPER
(all-E)-12-Iodoretinal [(all-E)-4]: The procedure was the same as
that described for the preparation of (all-E)-2. DIBAL-H
(0.54 mmol, 1.0  in hexane) reduction of pure (all-E)-12-iodoreti-
was then added and the resulting solution was stirred and warmed
to Ϫ40 °C over 1 h. Subsequently, homogeneous basic wet alumina
(Al2O3/water, 5:1, wt/wt; 0.56 g) was added and the mixture was
nonitrile [(all-E)-10] (88 mg, 0.22 mmol) gave (11Z)-12-iodoretinal stirred for an additional hour at 0 °C. The reaction mixture was
[(all-E)-4]; 84 mg (95%). 1H NMR (300.1 MHz, CD3OD): δ ϭ 0.99
dried by adding a mixture K2CO3/MgSO4 (1:9, wt/wt). All solids
(s, 6 H, H-16, H-17), 1.29 (m, 2 H, H-2), 1.46 (m, 2 H, H-3), 1.63 were filtered off and washed with diethyl ether to give (13Z)-14-
(s, 3 H, H-18), 1.88 (m, 2 H, H-4), 1.98 (s, 3 H, H-19), 2.36 (s, 3 chlororetinal [(13Z)-15]; 38 mg (95%). 1H NMR (300.1 MHz,
3
H, H-20), 5.94 (d, JH14,H15 ϭ 7.8 Hz, 1 H, H-14), 6.00 (d, CD3OD): 1.02 (s, 6 H, H-16, H-17), 1.48 (m, 2 H, H-2), 1.62 (m,
3
3JH8,H7 ϭ 16.1 Hz, 1 H, H-8), 6.02 (d, JH10,H11 ϭ 11.3 Hz, 1 H,
2 H, H-3), 1.69 (s, 3 H, H-18), 1.96 (m, 2 H, H-4), 2.03 (s, 3 H, H-
3
3
3
H-10), 6.34 (d, JH7,H8 ϭ 16.1 Hz, 1 H, H-7), 7.25 (d, JH11,H10
ϭ
19), 2.30 (s, 3 H, H-20), 5.75 (d, JH10,H11 ϭ 11.8 Hz, 1 H, H-10),
3
3
3
11.3 Hz, 1 H, H-11), 10.0 (d, JH15,H14 ϭ 7.8 Hz, 1 H, H-15) ppm.
6.12 (d, JH8,H7 ϭ 16.1 Hz, 1 H, H-8) 6.37 (d, JH7,H8 ϭ 16.1 Hz,
13C NMR (75.5 MHz, H-noise-decoupled, CD3OD): δ ϭ 12.7 (C-
1 H, H-7), 6.90 (d, JH12,H11 ϭ 12.5 Hz, 1 H, H-12), 7.06 (dd,
1
3
19), 18.1 (C-20), 20.3 (C-3), 21.9 (C-18), 29.3 (C16, C17), 33.9 (C- 3JH11,H10 ϭ 11.8, 3JH11,H12 ϭ 12.5 Hz, 1 H, H-11), 9.98 (s, 1 H, H-
4), 35.2 (C-1), 40.7 (C-2), 99.1 (C-12), 126.3 (C-10), 129.8 (C-14),
130.8 (C-7), 138.3 (C-8), 139.4 (C-11), 139.1 (C-6), 139.0 (C-5), 13.9 (C-19), 20.1 (C-20), 20.2 (C-3), 21.2 (C-18), 29.6 (C16, C17),
15) ppm. 13C NMR (75.5 MHz, 1H-noise-decoupled, CD3OD): δ ϭ
144.4 (C-9), 160.7 (C-13), 193.5 (C-15) ppm.
34.0 (C-4), 35.4 (C-1), 40.7 (C-2), 125.7 (C-7), 129.7 (C-12), 124.9
(C-10), 131.2 (C-5), 131.1 (C-11), 134.7 (C-14), 138.9 (C-8), 139.4
(C-6), 144.1 (C-9), 157.0 (C-13), 189.4 (C-15) ppm.
(11Z,13Z)-14-Chlororetinal [(11Z13Z)-15]: A solution of 4-(di-
phenoxyphosphoryl)-3-methyl-2-butenenitrile
(5;
244 mg,
0.78 mmol) in THF (10 mL) was added dropwise onto sodium hy-
dride (32 mg, 0.78 mmol) in THF (5 mL) at 0 °C. The mixture was
(11Z,13Z)-14-Bromoretinal [(11Z13Z)-16]: The procedure was the
same as that described for the preparation of (11Z,13Z)-15 and
stirred at 0 °C for 1 h. After that, NCS (104 mg, 0.78 mmol) in (13Z)-15 by adding 4-(diphenoxyphosphoryl)-3-methyl-2-butenen-
THF (10 mL) was added. After stirring at 0 °C for an additional 1
h, sodium hydride (30 mg, 0.74 mmol) in THF (10 mL) was added
itrile (5; 244 mg, 0.78 mmol) in THF (10 mL) dropwise to sodium
hydride (32 mg, 0.78 mmol) at 0 °C, followed by NBS (104 mg,
to the mixture. The temperature was allowed to gradually rise to 0.78 mmol) in THF (10 mL). After addition of sodium hydride
room temperature, followed by addition of β-(ionylidene)acetal- (30 mg, 0.74 mmol) in THF (10 mL) to the mixture, the tempera-
dehyde (7; 170 mg, 0.78 mmol) in THF (10 mL). The reaction mix- ture was allowed to gradually rise to room temperature. β-(Ionylid-
ture was then quenched with saturated aqueous NaHCO3. The
ene)acetaldehyde (7; 170 mg, 0.78 mmol) in THF (10 mL) was then
aqueous layer was extracted with diethyl ether (2 ϫ 15 mL) and
added. After workup, the crude product was found to be a com-
the combined organic layers were washed with brine, dried with plete conversion mixture of (11Z,13Z)-14-bromoretinonitrile
K2CO3/MgSO4 (1:9, wt/wt), filtered and concentrated under re-
duced pressure. The crude product was found to be a complete
conversion mixture of (11Z,13Z)-11 and (13Z)-14-chlororetinonitr-
[(11Z,13Z)-14-12] and (13Z)-14-bromoretinonitrile [(13Z)-14-12] in
an isomeric ratio of 3:2 and the corresponding 12-brominated reti-
nonitriles (11Z)-9 and (all-E)-9 in a ratio of 3:2. Pure (11Z,13Z)-
ile [(13Z)-11], in an isomeric ratio of 3:2, and the corresponding 14-bromoretinonitrile [(11Z,13Z)-14-12] (94 mg) and pure (13Z)-
12-chlorinated retinonitriles (all-E)-8 and (11Z)-8 in an isomeric 14-bromoretinonitrile [(13Z)-14-12] (63 mg; 59%) and correspond-
ratio of 3:2. Pure (11Z,13Z)-14-chlororetinonitrile [(11Z,13Z)-11] ing pure (11Z)-9 (40 mg) and (all-E)-9 (59 mg; 37%) were obtained
(58 mg) and (13Z)-14-chlororetinonitrile [(13Z)-11] (41 mg) were
obtained by preparative HPLC (58%). Pure (11Z)-8 (29 mg) and
by preparative HPLC. Subsequent DIBAL-H (0.65 mmol, 1.0 
in hexane) reduction of the pure (11Z,13Z)-14-bromoretinonitrile
pure (all-E)-8 (41 mg) were also obtained (39%). Pure (11Z,13Z)- [(11Z,13Z)-14-12] (94 mg, 0.26 mmol) yielded (11Z,13Z)-14-
1
14-chlororetinonitrile [(11Z,13Z)-11] (58 mg, 0.2 mmol) was dis-
bromoretinal [(11Z,13Z)-16]; 88 mg (94%). H NMR (300.1 MHz,
solved in dry petroleum ether (10 mL) and cooled to Ϫ80 °C. CD3OD): δ ϭ 1.03 (s, 6 H, H-16, H-17), 1.451(m, 2 H, H-2), 1.65
DIBAL-H (0.46 mmol, 1.0  in hexane) was added and the re-
sulting solution was stirred and warmed to Ϫ40 °C over 1 h.
Homogeneous basic wet alumina (0.81 g; Al2O3/water, 5:1, wt/wt) 8), 6.27 (d, JH10,H11 ϭ 11.5 Hz, 1 H, H-10), 6.43 (d, JH7,H8
was added, and the mixture was stirred at 0 °C for an additional 1
h. The reaction mixture was then dried with K2CO3/MgSO4 (1:9, 1 H, H-11), 7.28 (d, JH12,H11 ϭ 12.1 Hz, 1 H, H-12), 9.63 (s, 1 H,
(m, 2 H, H-3), 1.71 (s, 3 H, H-18), 2.02 (m, 2 H, H-4), 2.04 (s, 3
3
H, H-19), 2.25 (s, 3 H, H-20), 6.18 (d, JH8,H7 ϭ 16.1 Hz, 1 H, H-
3
3
ϭ
16.1 Hz, 1 H, H-7), 6.76 (dd, 3JH11,H10 ϭ 11.5, 3JH11,H12 ϭ 12.1 Hz,
3
1
wt/wt). All solids were filtered off and washed with diethyl ether to
H-15) ppm. 13C NMR (75.5 MHz, H-noise-decoupled, CD3OD):
give (11Z,13Z)-14-chlororetinal [(11Z,13Z)-15]; 55 mg (95%). 1H
δ ϭ 12.9 (C-19), 18.6 (C-20), 20.3 (C-3), 21.9 (C-18), 29.3 (C16,
NMR (300.1 MHz, CD3OD): δ ϭ 1.03 (s, 6 H, H-16, H-17), 1.49 C17), 34.2 (C-4), 35.2 (C-1), 40.9 (C-2), 124.3 (C-14), 129.3 (C-12),
(m, 2 H, H-2), 1.63 (m, 2 H, H-3), 1.68 (s, 3 H, H-18), 1.99 (m, 2
H, H-4), 2.02 (s, 3 H, H-19), 2.32 (s, 3 H, H-20), 6.05 (d,
130.6 (C-10), 131.5 (C-7), 137.3 (C-8), 138.6 (C-11), 139.1 (C-6),
139.0 (C-5), 144.4 (C-9), 152.9 (C-13), 184.8 (C-15) ppm.
3
3JH10,H11 ϭ 11.7 Hz, 1 H, H-10), 6.32 (d, JH8,H7 ϭ 16.1 Hz, 1 H,
3
3
(13Z)-14-Bromoretinal [(13Z)-16]: The procedure was the same as
that described for the preparation of (all-E)-8. DIBAL-H
(0.44 mmol, 1.0  in hexane) reduction of the pure (13Z)-retinon-
itrile (63 mg, 0.18 mmol) yielded (13Z)-14-bromoretinal [(13Z)-16
isomer]; 61 mg (97%). 1H NMR (300.1 MHz, CD3OD): δ ϭ 1.04
(s, 6 H, H-16, H-17), 1.48 (m, 2 H, H-2), 1.64 (m, 2 H, H-3), 1.71
(s, 3 H, H-18), 2.02 (m, 2 H, H-4), 2.07 (s, 3 H, H-19), 2.49 (s, 3
H-8) 6.39 (d, JH7,H8 ϭ 16.1 Hz, 1 H, H-7), 6.59 (d, JH12,H11
ϭ
3
3
12.5 Hz, 1 H, H-12), 6.96 (dd, JH11,H10 ϭ 11.7, JH11,H12
ϭ
12.5 Hz, 1 H, H-11), 9.93 (s, 1 H, H-15) ppm. 13C NMR
(75.5 MHz, 1H-noise-decoupled, CD3OD): δ ϭ 12.7 (C-19), 18.7
(C-20), 20.1 (C-3), 21.0 (C-18), 29.4 (C16, C17), 34.1 (C-4), 35.4
(C-1), 40.7 (C-2), 127.3 (C-7), 126.9 (C-10), 129.7 (C-12), 131.1 (C-
5), 131.9 (C-11), 133.6 (C-14), 138.3 (C-8), 138.8 (C-6), 142.1 (C-
9), 159.1 (C-13), 187.9 (C-15) ppm.
3
H, H-20), 6.22 (d, JH8,H7 ϭ 16.1 Hz, 1 H, H-8), 6.32 (d,
3
3JH10,H11 ϭ 11.6 Hz, 1 H, H-10), 6.45 (d, JH7,H8 ϭ 16.1 Hz, 1 H,
3
(13Z)-14-Chlororetinal [(13Z)-15]: (13Z)-14-Chlororetinonitrile,
H-7), 7.06 (d, JH12,H11 ϭ 15.0 Hz, 1 H, H-12), 7.49 (dd,
(13Z)-11 (41 mg, 0.15 mmol) was dissolved in dry petroleum ether 3JH11,H10 ϭ 11.5, 3JH11,H12 ϭ 15.0 Hz, 1 H, H-11), 9.84 (s, 1 H, H-
and cooled to Ϫ80 °C. DIBAL-H (0.32 mmol, 1.0  in hexane) 15) ppm. 13C NMR (75.5 MHz, 1H-noise-decoupled, CD3OD): δ ϭ
5106
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2004, 5100Ϫ5110

Preparation of a Series of 12- and 14-Haloretinals
FULL PAPER
13.1 (C-19), 15.6 (C-20), 20.3 (C-3), 22.0 (C-18), 29.4 (C16, C17), (10 mL) and CH3CN (10 mL). The resulting solution was stirred
34.1 (C-4), 35.2 (C-1), 40.8 (C-2), 124.6 (C-14), 131.2 (C-12), 131.5 at room temperature overnight and the reaction was then quenched
(C-10), 134.1 (C-7), 137.4 (C-11), 138.7 (C-8), 139.1 (C-6), 139.0
(C-5), 144.5 (C-9), 153.9 (C-13), 185.1 (C-15) ppm.
with saturated aqueous Na2CO3 (20 mL). The layers were sepa-
rated and the aqueous layer was extracted with diethyl ether (2 ϫ
20 mL). The combined organic layers were washed with brine, dried
with Na2SO4, filtered and the solvents evaporated. The crude prod-
uct was purified by flash chromatography (diethyl ether/petroleum
ether, 20:80, v/v) to give 3-(fluoromethyl)-5-(2Ј,6Ј,6Ј-trimethyl-1Ј-
cyclohexen-1Ј-yl)penta-2,4-dienenitrile (1.09 g, quantitative yield).
A solution of this compound (1.09 g, 4.7 mmol) in dry petroleum
ether (15 mL) was cooled to Ϫ60 °C, and DIBAL-H (1.8 mL, 1.0
 in hexane) was added. The resulting mixture was warmed to Ϫ40
°C over 1 h. Homogeneous wet silica gel (20.6 g; water/silica, 1:9,
wt/wt) was added and stirring was continued at 0 °C for 1 h. The
mixture was dried by adding Na2SO4, then all solids were filtered
off and washed with diethyl ether. The organic solvent was evapo-
rated and the residue was purified by column chromatography to
(11Z,13Z)-14-Iodoretinal [(11Z13Z)-17]: The procedure was the
same as that described for the preparation of (11Z,13Z)-11 and
(13Z)-11 by adding 4-(diphenoxyphosphoryl)-3-methyl-2-butenen-
itrile (5; 244 mg, 0.78 mmol) in THF (10 mL) dropwise to sodium
hydride (32 mg, 0.78 mmol) at 0 °C, followed by NIS (104 mg,
0.78 mmol) in THF (10 mL). After addition of further sodium hy-
dride (30 mg, 0.74 mmol) in THF (10 mL) to the mixture, the tem-
perature was allowed to gradually rise to room temperature. β-(Ion-
ylidene)acetaldehyde (7; 170 mg, 0.78 mmol) in THF (10 mL) was
then added. After workup, the crude product was found to be a
complete conversion mixture of (11Z,13Z)-14-iodoretinonitrile
[(11Z,13Z)-13] and (13Z)-14-iodoretinonitrile [(13Z)-13] in an iso-
meric ratio of 3:2 and the corresponding 12-iodinated retinonitriles
(11Z)-10 and (all-E)-10. Pure (11Z,13Z)-13 (131 mg) and pure
(13Z)-13 (88 mg) were isolated with a total yield of 73%; the corre-
sponding (11Z)-9 (29 mg) and (all-E)-9 (44 mg) isomers were ob-
tained with a total yield of 23% by preparative HPLC. DIBAL-H
(0.80 mmol, 1.0  in hexane) reduction of the pure (11Z,13Z)-14-
iodoretinonitrile (131 mg, 0.32 mmol) yielded (11Z,13Z)-14-iodor-
etinal [(11Z,13Z)-17]; 101 mg (77%). 1H NMR (300.1 MHz,
CD3OD): δ ϭ 1.02 (s, 6 H, H-16, H-17), 1.48 (m, 2 H, H-2), 1.63
(m, 2 H, H-3), 1.70 (s, 3 H, H-18), 1.98 (s, 3 H, H-19), 2.03 (m, 2
1
yield 34 (1.0 g, 91%). H NMR (300.1 MHz, CD3OD): δ ϭ 1.03
(s, 6 H, 2 ϫ CH3-6Ј), 1.48 (m, 2 H, H-5Ј), 1.63 (m, 2 H, H-4Ј), 1.81
2
(s, 3 H, 2Ј-CH3), 2.08 (m, 2 H, H-3Ј), 5.29 (d, JH6F6 ϭ 7.8 Hz, 2
3
3
H, H-6), 5.43 (d, JH2H1 ϭ 7.8 Hz, 1 H, H-2), 6.13 (d, JH4,H5
ϭ
3
16.5 Hz, 1 H, H-4), 6.47 (d, JH5,H4 ϭ 16.5 Hz, 1 H, H-5), 10.1 (d,
3JH1,H2 ϭ 7.8 Hz, 1 H, H-1) ppm. 13C NMR (75.5 MHz, 1H-noise-
decoupled, CDCl3): δ ϭ 18.6 (C-4Ј), 22.3 (C-2ЈϪCH3), 31.2 (2 ϫ
1
6Ј-CH3), 35.1 (C-3Ј), 35.3 (C-6Ј), 39.1 (C-5Ј), 81.3 (d, JC6,F6
ϭ
175.3 Hz, C-6), 124.5 (d, 3JC2,F6 ϭ 6.4 Hz, C-2), 133.8 (C-4), 135.3
(C-2Ј), 136.6 (C-1Ј), 137.1 (d, C-5), 153.3 (d, JC2,F6 ϭ 16.4 Hz, C-
2
3
H, H-4), 2.27 (s, 3 H, H-20), 5.98 (d, JH10,H11 ϭ 11.0 Hz, 1 H, H-
3), 189.7 (d, C-1) ppm.
3
3
10), 6.17 (d, JH8,H7 ϭ 16.0 Hz, 1 H, H-8), 6.37 (d, JH7,H8
ϭ
3
16.0 Hz, 1 H, H-7), 6.57 (d, JH12,H11 ϭ 12.5 Hz, 1 H, H-12), 6.77
(11Z,13Z)-14-Fluororetinal [(11Z,13Z)-20]: A solution of 4-(di-
(d, JH11,H10 ϭ 11.0, 3JH11,H12 ϭ 11.9 Hz, 1 H, H-11), 9.96 (s, 1 H,
3
phenoxyphosphoryl)-3-methyl-2-buteneintrile
(5;
122 mg,
H-15) ppm. 13C NMR (75.5 MHz, H-noise-decoupled, CD3OD):
1
0.39 mmol) in THF (5 mL) was added dropwise to sodium hydride
(16 mg, 0.39 mmol) at 0 °C. The mixture was stirred at 0 °C for 1 h.
Selectfluor (138 mg, 0.39 mmol) in THF (10 mL) was then added.
After stirring at 0 °C for 1 h, sodium hydride (15 mg, 0.37 mmol)
in THF (10 mL) was added to the mixture. The temperature was
allowed to gradually rise to room temperature. After addition of β-
(ionylidene)acetaldehyde (7; 85 mg, 0.39 mmol) in THF (5 mL) the
reaction mixture was quenched with saturated aqueous NaHCO3.
The aqueous layer was extracted with diethyl ether (2 ϫ 15 mL)
and the combined organic layers were washed with brine, dried
with a mixture of K2CO3 and MgSO4 (1:9, wt/wt), filtered and
concentrated under reduced pressure. The crude product was found
to contain (11Z,13Z)-14-fluororetinonitrile [(11Z,13Z)-19] and
(13Z)-14-fluororetinonitrile [(13Z)-19] in an isomeric ratio of 3:2.
Pure (11Z,13Z)-19 (62 mg) and pure (13Z)-19 (41 mg) were ob-
tained by preparative HPLC (93%). The pure (11Z,13Z)-retino-
nitrile (62 mg, 0.15 mmol) was dissolved in dry petroleum ether
(10 mL) and cooled to Ϫ80 °C. DIBAL-H (0.54 mmol, 1.0  in hex-
ane) was added and the resulting solution was stirred and warmed
to Ϫ40 °C over 1 h. Homogeneous basic wet alumina (0.95 g;
Al2O3/water, 5:1, wt/wt) was then added and the mixture was
stirred at 0 °C for an additional 1 hour. The reaction mixture was
dried with K2CO3/MgSO4 (1:9, wt/wt). All solids were filtered off
and washed with diethyl ether to yield (11Z,13Z)-14-fluororetinal
δ ϭ 12.7 (C-19), 18.3 (C-20), 20.1 (C-3), 21.7 (C-18), 29.4 (C16,
C17), 34.0 (C-4), 35.1 (C-1), 40.8 (C-2), 99.1(C-14), 127.8 (C-7),
131.1 (C-5), 132.3 (C-10), 135.3 (C-8), 137.4 (C-11), 138.8 (C-12),
139.1 (C-6), 141.4 (C-9), 159.3 (C-13), 189.6 (C-15) ppm.
(13Z)-14-Iodoretinal [(13Z)-17]: The procedure was the same as
that described for the preparation of (all-E)-8. DIBAL-H
(0.55 mmol, 1.0  in hexane) reduction of the pure (13Z)-14-iodor-
etinonitrile [(13Z)-13] (88 mg, 0.22 mmol) yielded (13Z)-17; 62 mg
(70%). 1H NMR (300.1 MHz, CD3OD): δ ϭ 1.03 (s, 6 H, H-16, H-
17), 1.46 (m, 2 H, H-2), 1.63 (m, 2 H, H-3), 1.69 (s, 3 H, H-18),
2.01 (s, 3 H, H-19), 2.03 (m, 2 H, H-4), 2.34 (s, 3 H, H-20), 6.07
(d, 3JH8,H7 ϭ 16.0 Hz, 1 H, H-8), 6.18 (d, 3JH10,H11 ϭ 11.5 Hz, 1 H,
H-10), 6.56 (d, 3JH12,H11 ϭ 15.2 Hz, 1 H, H-12), 6.77 (d, 3JH7,H8 ϭ
3
3
16.0 Hz, 1 H, H-7), 7.19 (d, JH11,H10 ϭ 11.5, JH11,H12 ϭ 15.2 Hz,
1 H, H-11), 9.99 (s, 1 H, H-15) ppm. 13C NMR (75.5 MHz, 1H-
noise-decoupled, CD3OD): δ ϭ 12.9 (C-19), 18.3 (C-20), 20.3 (C-
3), 22.0 (C-18), 29.4 (C16, C17), 33.9 (C-4), 35.2 (C-1), 40.7 (C-2),
99.7 (C-14), 130.6 (C-7), 131.0 (C-5), 132.3 (C-10), 136.3 (C-8),
137.4 (C-11), 138.2 (C-12), 138.3 (C-6), 140.1 (C-9), 160.2 (C-13),
190.3 (C-15) ppm.
3-(Fluoromethyl)-5-(2Ј,6Ј,6Ј-trimethyl-1Ј-cyclohexen-1Ј-yl)penta-2,4-
dien-1-al (34): 3-Methyl-5-(2Ј,6Ј,6Ј-trimethyl-1Ј-cyclohexen-1Ј-yl)p-
enta-2,4-dienenitrile (32; 1 g, 4.7 mmol) in freshly distilled dry THF [(11Z,13Z)-20], 60 mg (96%). 1H NMR (300.1 MHz, CD3OD): δ ϭ
(10 mL) was added dropwise, at Ϫ78 °C, to a solution of LDA
1.03 (s, 6 H, H-16, H-17), 1.49 (m, 2 H, H-2), 1.64 (m, 2 H, H-3),
prepared from freshly distilled diisopropylamine (0.5 g, 4.9 mmol) 1.69 (s, 3 H, H-18), 2.00 (m, 2 H, H-4), 2.03 (s, 3 H, H-19), 2.36
4
3
and n-butyllithium (2.9 mL, 1.6  in hexane) in THF (10 mL).
After stirring at this temperature for 30 min, freshly distilled tri-
(d, JH20,F14 ϭ 3.40 Hz, 3 H, H-20), 6.16 (d, JH8,H7 ϭ 16.1 Hz, 1
H, H-8), 6.38 (d, 3JH7,H8 ϭ 16.0 Hz, 1 H, H-7), 6.45 (d, 3JH12,H11 ϭ
3
3
methylsilyl chloride (0.51 g, 4.7 mmol) in THF (10 mL) was added 12.6 Hz, 1 H, H-12), 6.84 (dd, JH11,H10 ϭ 11.6, JH11,H12
ϭ
through a syringe. The resulting mixture was warmed to room tem-
perature over 2 h. Then the trimethylsilyl derivative 33 was treated
by adding Selectfluor (1.66 g, 4.7 mmol) in a mixture of dry THF
12.6 Hz, 1 H, H-11), 7.26 (d, 3JH10,H11 ϭ 11.6 Hz, 1 H, H-10), 9.81
3
(d, JH15,F14 ϭ 18.0 Hz, 1 H, H-15) ppm. 13C NMR (75.5 MHz,
1H-noise-decoupled, CD3OD): δ ϭ 10.8 (d, 3JC20,F14 ϭ 1.54 Hz, C-
Eur. J. Org. Chem. 2004, 5100Ϫ5110
www.eurjoc.org
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
5107

Y. Wang, J. Lugtenburg
20), 12.7 (C-19), 20.1 (C-3), 21.3 (C-18), 29.4 (C16, C17), 34.1 (C- aqueous NaHCO3. The aqueous layer was extracted with aceto-
FULL PAPER
3
4), 35.3 (C-1), 40.8 (C-2), 127.3 (d, JC12,F14 ϭ 12.5 Hz, C-12),
nitrile in diethyl ether (2 ϫ 50 mL, diethyl ether/acetonitrile, 10:1,
v/v) and the combined organic layers were washed with brine, dried
with MgSO4, filtered and concentrated under reduced pressure. The
crude product was purified by column chromatography (diethyl
ether/petroleum ether, 9:1, v/v) to give 28 (4.4 g, quantitative yield).
1H NMR (300.1 MHz, CD3OD): δ ϭ 1.15 (s, 3 H, H-8), 1.28 (s, 3
H, H-7), 2.13 (s, 3 H, H-6), 3.12 (s, 1 H, OH), 3.97 (s, 1 H, H-4),
5.31 (s, 1 H, H-2) ppm. 13C NMR (75.5 MHz, 1H-noise-decoupled,
CD3OD): δ ϭ 19.2 (C-6), 25.6 (C-7), 27.3 (C-8), 72.9 (C-5), 82.3
(C-4), 96.7 (C-2), 116.9 (C-CN), 163.3 (C-3) ppm. Corresponding
4
130.3 (C-10), 130.6 (C-7), 131.1 (C-5), 135.2 (d, JC11,F14
ϭ
7.67 Hz, C-11), 137.5 (C-8), 138.8 (C-6), 139.3 (C-9), 141.0 (C-13),
154.7 (d, 1JC14,F14 ϭ 262.3 Hz, C-14), 188.7 (d, 2JC15,F14 ϭ 26.1 Hz,
C-15) ppm.
(13Z)-14-Fluororetinal [(13Z)-20]: Pure (13Z)-19 (41 mg,
0.14 mmol) was dissolved in dry petroleum ether and cooled to
Ϫ80 °C. DIBAL-H (0.36 mmol, 1.0  in hexane) was added and
the resulting solution was stirred and warmed to Ϫ40 °C over 1 h.
Subsequently, homogeneous basic wet alumina (Al2O3/water, 5:1,
wt/wt; 0.63 g) was added and the mixture was stirred at 0 °C for
an additional 1 h. The reaction mixture was dried with K2CO3/
MgSO4 (1:9, wt/wt). All solids were filtered off and washed with
diethyl ether to yield (13Z)-14-fluororetinal [(13Z)-20]; 39 mg
(95%). 1H NMR (300.1 MHz, CD3OD): δ ϭ 1.03 (s, 6 H, H-16,
1
epoxide: H NMR (300.1 MHz, CD3OD): δ ϭ 1.16 (s, 3 H, H-8),
1.45 (s, 3 H, H-7), 2.11 (s, 3 H, H-6), 3.30 (s, 1 H, H-4), 5.27 (s, 1
H, H-2) ppm. 13C NMR (75.5 MHz, 1H-noise-decoupled,
CD3OD): δ ϭ 16.3 (C-6), 18.7 (C-7), 24.7 (C-8), 60.9 (C-5), 65.4
(C-4), 95.4 (C-2), 116.5 (C-CN), 157.9 (C-3) ppm.
H-17), 1.48 (m, 2 H, H-2), 1.63 (m, 2 H, H-3), 1.68 (s, 3 H, H-18), 3-Methyl-4-oxobut-2-enenitrile (29): Lead tetraacetate (15.1 g,
2.00 (m, 2 H, H-4), 2.02 (s, 3 H, H-19), 2.28 (d, 4JH20,F14 ϭ 3.08 Hz,
33.9 mmol) was added slowly to the stirred solution of 4,5-di-
3
3 H, H-20), 6.18 (d, JH8,H7 ϭ 16.1 Hz, 1 H, H-8), 6.28 (d, hydroxy-2-hexenenitrile (28; 4.4 g, 33.9 mmol) in dichloromethane
3
3JH10,H11 ϭ 11.4 Hz, 1 H, H-10), 6.39 (d, JH7,H8 ϭ 16.0 Hz, 1 H, (30 mL) at room temperature. Within 30 min TLC analysis indi-
3
H-7), 6.82 (d, JH12,H11 ϭ 15.2 Hz, 1 H, H-12), 7.27 (dd,
cated the complete conversion of the 4,5-diol to the aldehyde nitrile
(29). The reaction mixture was then filtered and subsequently
3
3JH11,H10 ϭ 11.5, JH11,H12 ϭ 15.2 Hz, 1 H, H-11), 9.82 (d,
1
3JH15,F14 ϭ 18.2 Hz, 1 H, H-15) ppm. 13C NMR (75.5 MHz, H- quenched with saturated aqueous NaHCO3. The aqueous layer was
noise-decoupled, CD3OD): δ ϭ 10.6 (d, 3JC20,F14 ϭ 1.58 Hz, C-20),
13.0 (C-19), 20.3 (C-3), 22.0 (C-18), 29.4 (C16, C17), 34.0 (C-4), layers were washed with brine, dried with MgSO4, filtered and con-
extracted with diethyl ether (2 ϫ 15 mL) and the combined organic
3
35.3 (C-1), 40.8 (C-2), 126.1 (d, JC12,F14 ϭ 12.7 Hz, C-12), 130.9
centrated under reduced pressure. The crude product was purified
4
(C-7), 131.1 (C-10), 131.3 (C-5), 134.7 (d, JC11,F14 ϭ 7.95 Hz, C- by column chromatography (diethyl ether/petroleum ether, 20:80,
1
11), 134.8 (C-6), 138.5 (C-8), 139.1 (C-9), 143.0 (C-13), 152.6 (d,
v/v) to give 29 (3.0 g, 91%). H NMR (300.1 MHz, CD3OD): δ ϭ
2
1JC14,F14 ϭ 262.1 Hz, C-14), 182.3 (d, JC15,F14 ϭ 28 Hz, C-15) 2.14 (s, 1 H, H-4), 6.18 (s, 1 H, H-2), 9.62 (s, 1 H, H-4) ppm, Ϫ
1
ppm.
13C NMR (75.5 MHz, H-noise-decoupled, CD3OD): δ ϭ 12.7 (C-
5), 114.4 (C-2), 115.7 (C-1), 155.8 (C-3), 190.3 (C-4) ppm.
3,5-Dimethyl-2,4-hexadienenitrile (27): n-Butyllithium (21 mL, 1.6
 in hexane) was added dropwise with a syringe to a solution of
2-(diethoxyphosphoryl)acetonitrile (21; 6 g, 33.9 mmol) in THF
4-(Diphenoxyphosphoryl)-4-hydroxy-3-methyl-2-butenenitrile (30):
A mixture of diphenyl phosphite (diphenyl phosphonate) (7.7 g,
(5 mL) at Ϫ 60 °C. The mixture was stirred at Ϫ60 °C for 1 h. 33 mmol) and 29 (3.0 g, 32 mmol) was refluxed at 131 °C for 6 h
1
Subsequently, 4-methyl-3-penten-2-one (26; 3.2 g, 33.9 mmol) in
until H NMR analysis indicated the reaction was complete. After
THF (15 mL) was added and the temperature was allowed to column chromatography (ethyl acetate/petroleum ether, 1:1, v/v),
1
gradually rise to room temperature. The reaction mixture was then
quenched with saturated aqueous NH4Cl. The aqueous layer was
extracted with diethyl ether (2 ϫ 30 mL) and the combined organic
layers were washed with brine, dried with MgSO4, filtered and con-
centrated under reduced pressure. The crude product was purified
by column chromatography (diethyl ether/petroleum ether, 20:80,
v/v) to give 27 (3.9 g, quantitative yield). 1H NMR (300.1 MHz,
30 (9.1 g, 86%) was obtained. H NMR (300 MHz, CD3OD): δ ϭ
2.25 (m, 3 H, H-5, cis), 2.37 (m, 3 H, H-5, trans), 3.12 (m, 1 H,
ϪOH, cis and trans), 4.75 (dd, J ϭ 23.7 Hz, 1 H, H-4, trans), 5.49
(dd, J ϭ 24.0 Hz, 1 H, H-4, cis), 5.77 (m, 2 H, H-2, cis and trans),
7.24 (m, 10 H, arom.) ppm. 13C NMR (75.5 MHz, 1H-noise-decou-
pled, CDCl3): δ ϭ 22.5 (C-5, cis), 24.3 (C-5, trans), 34.7 (dd,
1JC4,P4 ϭ 97.9 Hz, C-4, trans), 36.5 (dd, JC4,P4 ϭ 97.9 Hz, C-4,
1
CD3OD): δ ϭ 1.13 (s, 3 H, H-8), 1.32 (s, 3 H, H-7), 2.21 (s, 3 H, cis), 101.5 (C-2, cis), 102.7 (C-2, trans), 115.1 (C-1, trans, C-1, cis),
H-6), 5.17 (s, 1 H, H-4), 5.53 (s, 1 H, H-2) ppm,. 13C NMR
121.4 (C-2Ј, trans, C-2Ј, cis; C-6Ј, trans, C-6Ј, cis), 125.8 (C-4Ј,
(75.5 MHz, 1H-noise-decoupled, CD3OD): δ ϭ 19.3 (C-8), 25.1 (C- trans, C-4Ј, cis), 129.8 (C-3Ј, trans, C-3Ј, cis; C-5Ј, trans, C-5Ј, cis),
7), 27.5 (C-6), 103.7 (C-2), 117.0 (C-CN), 123.6 (C-4), 136.9 (C-5), 149.8 (C-1Ј, trans, C-1Ј, cis), 154.8 (C-3, trans, C-3, cis) ppm.
163.1 (C-3) ppm.
4-(Diphenoxyphosphoryl)-4-fluoro-3-methyl-2-butenenitrile
DAST (1.3 g, 8.1 mmol) was added dropwise through a syringe to
benzoic acid (mCPBA; 12.5 g, 51 mmol) was added slowly to a a solution of 30 (2.3 g, 66 mmol) in dichloromethane (15 mL) at
(31):
4,5-Dihydroxy-3,5-dimethyl-2-hexenenitrile (28): meta-Chloroper-
stirred solution of 3,5-dimethyl-4-hexadienenitrile (27; 3.9 g,
33.9 mmol) in ethyl acetate (15 mL) at room temperature, and the
mixture was stirred at room temperature for 3 h until TLC analysis
indicated complete conversion. The reaction mixture was then
quenched with saturated aqueous NaOH. The aqueous layer was
extracted with diethyl ether (2 ϫ 30 mL) and the combined organic
layers were washed with brine, dried with MgSO4, filtered and con-
centrated under reduced pressure. Subsequently, perchloric acid
Ϫ80 °C. The resulting solution was slowly warmed to room tem-
perature overnight. Subsequently, the reaction mixture was
quenched with saturated aqueous NaHCO3. The aqueous layer was
extracted with dichloromethane (2 ϫ 30 mL) and the combined
organic layers were washed with brine, dried with MgSO4, filtered
and concentrated under reduced pressure. The crude product was
purified by column chromatography (ethyl acetate/petroleum ether,
1
1:1, v/v) to give 31 (0.67 g, 31%). H NMR (300 MHz, CD3OD):
(0.14 , 15 mL) in aqueous solution was added to the correspond- δ ϭ 2.18 (m, 3 H, H-5, cis), 2.23 (m, 3 H, H-5, trans), 5.27 (dd,
ing epoxide. After stirring at room temperature for 1 h, TLC analy-
sis indicated the complete conversion of the epoxide to the 4,5-diol.
Subsequently, the reaction mixture was quenched with saturated
J ϭ 23.9, J ϭ 47.2 Hz H-4, 1 H, trans), 5.46 (dd, J ϭ 22.3, J ϭ
47.2 H-4, 1 H, cis), 5.68 (m, 2 H, H-2, cis and trans), 7.19 (m, 10
H, arom.) ppm. 13C NMR (75.5 MHz, 1H-noise-decoupled,
5108
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2004, 5100Ϫ5110

Preparation of a Series of 12- and 14-Haloretinals
FULL PAPER
CDCl3): δ ϭ 23.8 (d, 3JC5,F4 ϭ 10.8 Hz, C-5, cis), 24.6 (d, 3JC5,F4 ϭ (dd, JH11,H10 ϭ 11.6, JH11,F12 ϭ 18.6 Hz, 1 H, H-11), 10.1 (d,
3
3
1
1
10.7 Hz, C-5, trans), 83.7 (dd, JC4,P4 ϭ 91.3, JC4,F4 ϭ 266.2 Hz,
3JH15,H14 ϭ 7.8 Hz, 1 H, H-15) ppm. 13C NMR (75.5 MHz, 1H-
1
1
3
C-4, trans), 86.4 (dd, JC4,P4 ϭ 91.3, JC4,F4 ϭ 266.2 Hz, C-4, cis),
101.3 (d, JC2,F4 ϭ 13.6 Hz, C-2, cis), 101.7 (d, JC2,F4 ϭ 13.6 Hz,
noise-decoupled, CD3OD): δ ϭ 12.9 (C-19), 18.3 (d, JC20,F12
ϭ
3
3
2.3 Hz, C-20), 20.3 (C-3), 21.0 (C-18), 29.4 (C16, C17), 34.0 (C-4),
3
C-2, trans), 113.1 (C-1, trans, C-1, cis), 120.3 (C-2Ј, trans, C-2Ј, cis; 35.4 (C-1), 40.7 (C-2), 123.7 (d, JC11,F12 ϭ 18.2 Hz, C-11), 126.3
C-6Ј, trans, C-6Ј, cis), 124.5 (C-4Ј, trans, C-4Ј, cis), 126.3 (C-3Ј, (C-7), 127.9 (d, JC14,F12 ϭ 11.8 Hz, C-14), 129.1 (d, JC10,F12
3
3
ϭ
trans, C-3Ј, cis; C-5Ј, trans, C-5Ј, cis), 148.7 (C-1Ј, trans, C-1Ј, cis), 6.8 Hz, C-10), 131.3 (C-5), 138.8 (C-8), 138.1 (C-6), 139.3 (C-9),
2
3
1
154.2 (d, JC3,F4 ϭ 28.6 Hz, C-3, trans, C-3, cis) ppm.
152.3 (d, JC13,F12 ϭ 26 Hz, C-13), 157.8 (d, JC12,F12 ϭ 261.1 Hz,
4
C-12), 189.7 (d, JC15,F12 ϭ 2.6 Hz, C-15) ppm.
(11Z)-12-Fluororetinal [(11Z)-1]: A solution of 4-(diphenoxyphos-
phoryl)-4-fluoro-3-methyl-2-butenenitrile (31; 131 mg, 0.39 mmol)
in THF (5 mL) was added dropwise to sodium hydride (15 mg,
0.37 mmol) at 0 °C. The mixture was stirred at 0 °C for 1 h and
then the temperature was allowed to gradually rise to room tem-
perature. β-(Ionylidene)acetaldehyde (7; 85 mg, 0.39 mmol) in THF
(5 mL) was then added and the reaction mixture was quenched
with saturated aqueous NaHCO3. The aqueous layer was extracted
with diethyl ether (2 ϫ 15 mL) and the combined organic layers
were washed with brine, dried with a mixture of K2CO3 and
MgSO4 (1:9, wt/wt), filtered and concentrated under reduced press-
ure. The crude product was found to contain (11Z)-12-fluororeti-
nonitrile and (all-E)-12-fluororetinonitrile in an isomeric ratio of
2:3. Pure (11Z)-12-fluororetinonitrile (40 mg) and pure (all-E)-12-
fluororetinonitrile (61 mg) were obtained by preparative HPLC
(96%). Pure (11Z)-12-fluororetinonitrile (40 mg, 0.14 mmol) was
dissolved in dry petroleum ether and cooled to Ϫ80 °C. DIBAL-
H (0.35 mmol, 1.0  in hexane) was added and the resulting solu-
tion was stirred and warmed to Ϫ40 °C in 1 h. Then, homogeneous
basic wet alumina (Al2O3/water, 5:1, wt/wt; 0.61 g) was added and
the mixture was stirred at 0 °C for an additional 1 h. The mixture
was then dried with a mixture of K2CO3 and MgSO4 (1:9, wt/wt).
All solids were filtered off and washed with diethyl ether to yield
(11Z)-12-fluororetinal [(11Z)-1]; 39 mg (98%). 1H NMR
(300.1 MHz, CD3OD): δ ϭ 1.02 (s, 6 H, H-16, H-17), 1.48 (m, 2
H, H-2), 1.64 (m, 2 H, H-3), 1.70 (s, 3 H, H-18), 2.02 (m, 2 H, H-
Acknowledgments
This investigation was supported by the Netherlands Foundation
for Chemical Research (SON) with financial aid from the Nether-
lands Organisation for Scientific Research (NWO). The authors
wish to thank F. Lefeber and C. Erkelens for recording the NMR
spectra, Prof. Dr. R. A. Mathies, Prof. Dr. H. J. M. de Groot and
Dr. E. M. Blokhuis for fruitful discussions, and Dr. R. van der
Steen for careful reading of the final manuscript.
[1]
S. Watson, S. Arkinstall, in The G-Protein Linked Receptor
Facts Book, Academic Press, San Diego, 1994.
[2]
L. Tang, T. G. Ebrey, S. Subramaniam, Isr. J. Chem. 1995,
35, 193Ϫ209.
[3]
I. R. Pogozheva, A. L. Lomize, H. I. Mosberg, Biophys. J.
1997, 1963Ϫ1985.
P. J. E. Verdegem, J. Lugtenburg, H. J. M. De Groot, in Pharm-
[4]
acochemistry Library, Stable Isotopes in Pharmaceutical Re-
search (Eds.: T. R. Browne, H. E. Timmerman), Elsevier, Am-
sterdam,, 1997 p. 2Ϫ14.
[5]
F. L. A. Creemers, K. K. Suzanne, P. H. M. Bovee-Geurts, W.
J. DeGrip, J. Lugtenburg, H. J. M. de Groot, Proc. Natl. Acad.
Sci. USA 2002, 99, 9101Ϫ9106.
P. J. E. Verdegem, M. Helmle, J. Lugtenburg, H. J. M. de
4
4), 2.03 (s, 3 H, H-19), 2.37 (d, JH20,F12 ϭ 3.40 Hz, 3 H, H-20),
[6]
3
4
6.03 (dd, JH14,H11 ϭ 7.9, JH14,F12 ϭ 7.6 Hz, 1 H, H-14), 6.12 (d,
3JH8,H7 ϭ 16.1 Hz, 1 H, H-8), 6.27 (d, JH10,H11 ϭ 11.5 Hz, 1 H,
3
Groot, J. Am. Chem. Soc. 1997, 119, 169Ϫ174.
Y. Wang, W. S. Woo, I. van der Hoef, J. Lugtenburg, Eur. J.
[7]
H-10), 6.79 (d, 3JH7,H8 ϭ 16.0 Hz, 1 H, H-7), 7.13 (dd, JH11,H10 ϭ
3
Org. Chem. 2004, 2166Ϫ2175.
3
3
11.5, JH11,F12 ϭ 26.8 Hz, 1 H, H-11), 10.2 (d, JH15,H14 ϭ 7.9 Hz,
[8]
Y. Wang, J. Lugtenburg, Eur. J. Org. Chem. 2004, 3497Ϫ3510.
1 H, H-15) ppm. 13C NMR (75.5 MHz, 1H-noise-decoupled,
[9]
R. W. Schoenlein, L. A. Peteanu, R. A. Mathies, C. V. Shank,
3
CD3OD): δ ϭ 12.9 (C-19), 20.1 (d, JC20,F12 ϭ 2.6 Hz, C-20), 20.3
Science 1991, 254, 412Ϫ415.
R. S. H. Liu, L. U. Colmenares, Proc. Natl. Acad. Sci. USA
[10]
(C-3), 21.2 (C-18), 29.4 (C16, C17), 34.1 (C-4), 35.4 (C-1), 40.8
3
(C-2), 127.1 (C-7), 129.3 (d, JC14,F12 ϭ 11.7 Hz, C-14), 129.9 (d,
2003, 100, 14639Ϫ14644.
3
[11]
3JC10,F12 ϭ 7.2 Hz, C-10), 131.3 (C-5), 132.7 (d, JC11,F12
ϭ
R. S. H. Liu, A. E. Asato, Proc. Natl. Acad. Sci. USA 1985,
82, 259Ϫ263.
18.5 Hz, C-11), 137.8 (C-8), 138.1 (C-6), 141.2 (C-9), 151.4 (d,
[12]
1
3JC13,F12 ϭ 22.3 Hz, C-13), 157.3 (d, JC12,F12 ϭ 261.0 Hz, C-12),
R. A. Mathies, J. Lugtenburg, The Primary Photoreaction of
Rhodopsin, in Handbook of Biological Physics, vol. 3 (‘‘Molecu-
lar Mechanism of Vision’’) (Eds.: D. G. Stavenga, W. J. DeGrip,
E. N. Pugh Jr.), Elsevier Science Press, Amsterdam, 2000, p.
55Ϫ90.
4
190.3 (d, JC15,F12 ϭ 2.56 Hz, C-15) ppm.
(all-E)-12-Fluororetinal [(all-E)-1]: Pure (all-E)-12-retinonitrile
(61 mg, 0.21 mmol) was dissolved in dry petroleum ether and co-
oled to Ϫ80 °C. DIBAL-H (0.55 mmol, 1.0  in hexane) was added
and the resulting solution was stirred and warmed to Ϫ40 °C over
1 h. Then, homogeneous basic wet alumina (Al2O3/water, 5:1, wt/
wt; 0.94 g) was added and the mixture was stirred at 0 °C for an
additional 1 h. The mixture was dried with a mixture of K2CO3
and MgSO4 (1:9, wt/wt). All solids were filtered off and washed
with diethyl ether to yield (all-E)-12-fluororetinal [(all-E)-1]; 58 mg
[13]
P. J. E. Verdegem, P. H. M. Bovee-Geurts, W. J. DeGrip, J.
Lugtenburg, H. J. M. de Groot, Biochemistry 1999, 38,
11316Ϫ11324.
[14]
Alonso, E. J. Finn, Fundamental University Physics 1: Mech-
anics, Addison Wesley Publishing Company, Reading, Massa-
chusetts, 1967.
[15]
A. Cooper, Nature 1979, 282, 531Ϫ533.
[16]
G. G. Kochendoerfer, P. J. E. Verdegem, I. van der Hoef, J.
Lugtenburg, R. A. Mathies, Biochemistry 1996, 35,
1
(95%). H NMR (300.1 MHz, CD3OD): δ ϭ 1.03 (s, 6 H, H-16,
16230Ϫ16241.
H-17), 1.46 (m, 2 H, H-2), 1.63 (m, 2 H, H-3), 1.68 (s, 3 H, H-18),
[17]
B. S. Lee, S. Y. Lee, D. Y. Oh, J. Org. Chem. 2000, 65,
4175Ϫ4178.
M. F. Probst, A. M. Modro, T. A. Modro, Can. J. Chem. 1997,
75, 1131Ϫ1135.
1.98 (m, 2 H, H-4), 2.01 (s, 3 H, H-19), 2.28 (d, 4JH20,F12 ϭ 3.60 Hz,
3
[18]
3 H, H-20), 6.07 (d, JH8,H7 ϭ 16.1 Hz, 1 H, H-8), 6.11 (dd,
3JH14,H11 ϭ 7.8, 4JH14,F12 ϭ 7.6 Hz, 1 H, H-14), 6.23 (d, 3JH10,H11 ϭ
3
[19]
11.6 Hz, 1 H, H-10), 6.41 (d, JH7,H8 ϭ 16.0 Hz, 1 H, H-7), 6.56
R. P. Singh, J. M. Shreeve, Acc. Chem. Res. 2004, 37, 31Ϫ44.
Eur. J. Org. Chem. 2004, 5100Ϫ5110
www.eurjoc.org
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
5109

Y. Wang, J. Lugtenburg
FULL PAPER
[20]
[25]
[26]
P. J. E. Verdegem, M. C. F. Monnee, J. Lugtenburg, J. Org.
R. S. H. Liu, A. E. Asato, M. Denny, D. Mead, J. Am. Chem.
Soc. 1984, 106, 8298Ϫ8300.
M. Groesbeek, S. O. Smith, J. Org. Chem. 1997, 62,
3638Ϫ3641.
Chem. 2000, 66, 1269Ϫ1282.
A. C. C. van Wijk, M. B. van der Weerd, J. Lugtenburg, Eur.
[21]
J. Org. Chem. 2003, 863Ϫ868.
[22]
[27]
[28]
A. N. Pudovik, I. V. Konovalova, Synthesis 1979, 81Ϫ96.
S. Thibaudequ, V. Gouverneur, Org. Lett. 2003, 4891Ϫ4893.
F. J. Jansen, J. Lugtenburg, in Carotenoids, vol. 2 (Eds.: G. Brit-
ton, H. P. Pfawder, S. L. Jensen), Birkhäuser Verlag, Basel,
1996, p. 233Ϫ258.
[23]
V. P. Schenider, R. Jentzsch, G. W. Fischer, J. Prakt. Chem.
1974, 316, 1002Ϫ1012.
[24]
G. B. Hammond, D. J. deMendonca, J. Fluorine Chem. 2000,
102, 189Ϫ197.
Received July 12, 2004
5110
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2004, 5100Ϫ5110